Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency (STEP-OTC)

A Phase 1/2 Single Ascending Dose Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenously Administered MRT5201 in Subjects With Ornithine Transcarbamylase Deficiency

This Phase 1/2, first-in-human study will evaluate the safety and tolerability of single escalating doses of MRT5201 administered intravenously to subjects with OTC Deficiency (OTCD). This study will also evaluate the effect of a single dose of MRT5201 on metabolic markers of OTCD and ureagenesis; and determine an acceptable dosing interval of MRT5201.

Study Overview

• Status: Withdrawn
• Conditions: Ornithine Transcarbamylase Deficiency
• Intervention / Treatment: Biological: MRT5201; Other: Placebo

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have a documented diagnosis of OTCD.
• Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L

• Subject's OTCD is stable as evidenced by meeting the following criteria:

  • Ammonia level <175 µmol/L during the Screening Period and at Baseline (Day -1)
  • No clinical symptoms of hyperammonemia during the Screening Period and at Baseline (Day -1)
• If using nitrogen scavenger therapy, must be on a stable regimen for ≥28 days prior to signing informed consent
• Subject has maintained a stable protein restricted diet (which may or may not include medical foods) and/or amino acid supplementation with no changes in calorie or protein goals and no changes in medical food and/or amino acid supplementation for ≥ 28 days prior to signing informed consent.

Exclusion Criteria:

• Any laboratory abnormality that may put the subject at increased risk by participating in this study.

• Have any significant concurrent or past medical condition that would represent an unacceptable risk to the subject or might jeopardize the collection of high-quality data from the study. These include but are not limited to:

  • History of liver transplant, including hepatocyte therapy/transplant
  • History of liver disease
  • Positive viral serology test results for HIV type 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody
  • Type I or Type II diabetes that is poorly controlled, in the opinion of the Investigator
  • Poorly controlled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg)
  • Use of anticoagulants or platelet inhibitors, including but not limited to heparin and non-steroidal anti-inflammatory drugs (NSAIDS). Acetaminophen is permitted
• Participation in previous clinical studies evaluating investigational OTCD therapies directed at expressing functional OTC protein (eg, OTC gene therapy studies, other mRNA replacement therapy) that has led to the presence of anti-OTC antibodies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MRT5201; Single Ascending Low, Mid, and High doses of MRT5201	Biological: MRT5201; Codon-optimized human ornithine transcarbamylase messenger ribonucleic acid with lipid-based nanoparticles
Placebo Comparator: Placebo; Placebo comparator using 5% dextrose in water at the same administration rate as study drug.	Other: Placebo; 5% dextrose in water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of treatment-emergent adverse events by treatment group	The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) for each dosing cohort by treatment group, assessed by severity and relationship to study product.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics parameters of MRT5201	Pharmacokinetics of MRT5201 as measured by levels of mRNA	1 month after single dose
Effect of a single dose of MRT5201 on ureagenesis	Change from Baseline in 4-hour ureagenesis AUC at weeks 2, 3, 4, and 5 after a single dose of MRT5201	Up to 1 month after single dose
Effect of single dose of MRT5201 on metabolic markers of OTCD	Change from Baseline in 8-hour ammonia AUC	6 months after single dose

Collaborators and Investigators

• Sponsor: Translate Bio, Inc.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2019
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: November 28, 2018
• First Submitted That Met QC Criteria: December 4, 2018
• First Posted (Actual): December 6, 2018

Study Record Updates

• Last Update Posted (Actual): September 17, 2019
• Last Update Submitted That Met QC Criteria: September 12, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: UCD; OTC; Urea Cycle Disorder
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease
• Other Study ID Numbers: MRT5201-101; 2018-004095-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No